Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, fibrin-based adhesives do not covalently bind to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic (see for example Sehl et al., U.S. Patent Application Publication No. 2003/0119985 A1, and Goldmann, U.S. Patent Application Publication No. 2005/0002893 A1). These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups, which are capable of reacting with the nucleophilic groups of the first component, to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536 A1) describes hydrogel tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. These adhesives provide improved adhesion and cohesion properties, crosslink readily at body temperature, maintain dimensional stability initially, do not degrade rapidly, and are nontoxic to cells and non-inflammatory to tissue. However, for certain applications, a hydrogel tissue adhesive that forms more rapidly and degrades more rapidly is desired. For example, for use as a tissue adhesive or hemostat in a liver resection, rapid gelation is required to minimize blood loss and the hydrogel should degrade in a timely manner to prevent an inflammatory reaction. Additionally, if the hydrogel-forming precursors are delivered to a tissue surface using a spray device, rapid gelation is required so that the hydrogel forms in the desired location. The gelation rate can be increased by increasing the concentration of the reactive groups of the hydrogel precursors, but this leads to a hydrogel with a higher crosslink density which consequently degrades more slowly.
Figuly et al. (copending and commonly owned U.S. Patent Application Publication No. 2010/0112063 A1) describes the use of certain chemical additives which increase the gelation time to form a hydrogel tissue adhesive and decrease the degradation time of the resulting hydrogel.
Wagman et al. (copending and commonly owned U.S. Patent Application Publication No. 2010/0160960 A1) describes the use of a polyol additive to increase the degradation time of a hydrogel tissue adhesive.
Wagman et al. (copending and commonly owned U.S. Patent Application Publication No. 2012/0035129 A1) describes the use of an oligomer additive to decrease the degradation time of a hydrogel tissue adhesive, but the gelation time to form the hydrogel is not decreased.
In view of the above, a need exits for a hydrogel tissue adhesive which has an increased rate of gelation and an increased degradation rate.